Drivers and impact of the early silent invasion of SARS-CoV-2 Alpha

SARS-CoV-2 variants of concern (VOCs) circulated cryptically before being identified as a threat, delaying interventions. Here we studied the drivers of such silent spread and its epidemic impact to inform future response planning. We focused on Alpha spread out of the UK. We integrated spatio-temporal records of international mobility, local epidemic growth and genomic surveillance into a Bayesian framework to reconstruct the first three months after Alpha emergence. We found that silent circulation lasted from days to months and decreased with the logarithm of sequencing coverage. Social restrictions in some countries likely delayed the establishment of local transmission, mitigating the negative consequences of late detection. Revisiting the initial spread of Alpha supports local mitigation at the destination in case of emerging events.


Arrival times, number of passengers and sequencing coverage
Assuming exponential increase of cases in the origin country, the time of first arrival with passenger flow  is Gumbel distributed with mean proportional to  () 1 .Assuming collection coverage  on top, the mean arrival time based on first collection scales as  () +  ()   and "iso-arrival-time" lines are as  () +  () =  (anti diagonals).We report such lines in Fig. 1B as reference.

International dissemination model: Sensitivity analysis
In the sensitivity analysis we tested the following assumptions:  5 shows the results of the sensitivity analysis.For the baseline scenario and the sensitivity models tested we provide best estimates and some model predictions chosen as reference.Varying the parameters had little impact on the parameters estimated in the model.The number of countries with introduction before 31 Dec 2020 increased in the following cases: delays from collection to submission for Alpha computed for each country aggregated over 7 days, 25% detection of imported cases, no change of slope.

Local dynamics in the USA at a finer spatial scale
The analysis of Alpha local spread for the USA shows that this country is out of trend, with a high number of predicted Alpha cases compared with model estimates.Here, we carry out the comparison for two individual states, California and Florida, and for New York City -see sources of data reported in Supplementary Table 2.These locations were the port of entry of Alpha into the US, with early reported Alpha cases linked directly to the UK 2,3 .
As for the USA as a whole, the autochthonous model A was fed with importation fluxes estimated from the international dissemination model and we compared the model-predicted number of Alpha cases with the empirical estimates.We present these results on Supplementary Fig. 4.
For California and New York City, the comparison between model and empirical estimates follows a trend similar to European countries.Florida registered a high proportion of Alpha cases 2 .Such a high level of Alpha circulation can be compatible with model predictions in a scenario of early Alpha introduction, i.e. introduction dates close to the lower bound of the range predicted by the model.

Median seeding time
In the reference case in which traveling fluxes are constant in time and  -is the same in the destination country as in the UK, the reference median date of seeding would fall halfway between the date of emergence and 31 Dec 2020 (see Methods).The median seeding dates of active chains at the end of 2020 departed from this assumed scenario.In Fig. 4D, we found that there was a negative correlation between the overall reproduction ratio over the period and the difference between computed median seeding date and reference median seeding date (spearman correlation -0.81 with p-value = 0.049), implying that lower transmissibility overall led to less success in early introductions.In Supplementary Fig. 5 we show that there was no significant correlation between the international traffic drop and the difference of the median seeding date with the reference date.

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Mean incubation period equal to 4 days • Mean incubation period equal to 6 days • Delays computed for each countries after the alert averaged over a sliding time window of 7 days • Percentage of case detection outside the UK, Kc= 25% • Flights from all England airports with a catchment population of 56 millions inhabitants • No changepoint for the Alpha incidence exponential growth in the UK • Two changepoints for the Alpha incidence exponential growth in the UK an 5 Nov 2020 and 2 Dec 2020 Supplementary Table

Table 2 . Summary of data for the local spread analysis for
the locations within the US explored in Supplementary Fig.4. 9Supplementary